Sutherland and coworkers developed and used the spheroid model in the 1970s for radiobiological studies (1 –6 ). Spheroids are three-dimensional (spherical) clusters of tumor cells grown from one or several cell clones. The spheroid model contains many of the elements of a tumor xenograft including an extracellular matrix and cell-cell/cell-matrix interactions (7 –10 ); a spatial geometry that can produce well-defined drug and nutrient concentration gradients (11 ,12 ); subpopulations of cells that are quiescent, hypoxic, necrotic, or near-necrotic (13 ); and the potential to monitor response over a protracted time-period after different treatment schedules (14 ). These similarities to a tumor xenograft are coupled with many of the experimental advantages of a monolayer culture including the ability to rigorously control experimental and treatment conditions, the ability to investigate response and study mechanisms, and also the ability to investigate a large number of agents and combinations rapidly and at low cost.
